Novel 5-(n-substituted aminomethyl)-2-oxazolidinones and their process of preparation

ABSTRACT

5-AMINOMETHYL-2-OXAZOLIDINONES OF THE GENERAL FORMULA:   IN WHICH: REPRESENTS EITHER A DIALKYLAMINO RADICAL IN WHICH THE ALKYL PORTIONS HAVE ONE TO FIVE CARBON ATOMS, OR A HETEROCYCLIC AMINO RADICAL WHICH MAY BE SUBSTITUTED BY AN ALKYL RADICAL HAVING ONE TO FIVE CARBON ATOMS OR BY A PYRROLIDINOCARBONYLMETHYL RADICAL, AND R3 represents a phenyl radical which may be substituted by one or more of the following radicals: AN ALKOXY RADICAL HAVING ONE TO FIVE CARBON ATOMS; A HALOGEN ATOM; A TRIFLUOROMETHYL RADICAL, OR A CARBOXYL RADICAL WHICH MAY BE ESTERIFIED. The compound is made by reacting the corresponding 2-propanol derivative with ethyl carbonate. The compound possesses hypotensive, vasodilatatory, spasmolytic, sedative, myorelaxant, analgesic and anti-inflammatory properties.

United States Patent Fauran et al.

[451 Aug. 29, 1972 NOVEL S-(N-SUBSTITUTED AMINOMETHYL)-2-OXAZOLIDINONES AND THEIR PROCESS OF PREPARATION Inventors: Claude P. Fauran, Paris; Claude J. Gouret, Meudon; Guy M. Raynaud; Colette A. Donzon, both of Paris, all of France Assignee: S. A. Delalande, Regnanlt, France Filed: Oct. 2, 1969 Appl. No.: 863,354

Foreign Application Priority Data Oct. 22, 1968 Great Britain ..49,963/68 US. Cl. ....260/307 C, 260/2472 R, 260/268 H, 260/293.67, 424/248, 424/250, 424/267, 424/272 Int. Cl. ..C07d 85/28 Field of Search .260/307 C, 268 H, 294.3 B, 260/2472 B References Cited UNITED STATES PATENTS 5/1969 Budnowski ..260/307 OTHER PUBLICATIONS Ludwig et al., C. A. 49, l2442- 3 (1955). Zikolova et al., C. A. 62, 13135 (1965).

Primary Examiner-Alex Maze! Assistant Examiner-R. V. Rush Attorney-Woodhams, Blanchard and Flynn S-aminomethyl-Z-oxazolidinones of the general formula:

ABSTRACT in which:

a n to a roiilet iiyl radical, or

a carboxyl radical which may be esterified. The

compound is made by reacting the corresponding Z-propanol derivative with ethyl carbonate. The compound possesses hypotensive, vasodilatatory, spasmolytic, sedative, myorelaxant, analgesic and anti-inflammatory properties.

7 Claims, No Drawings 1 NOVEL S-(N-SUBSTI'IUTED AMINOMEPHYU-Z- 'OXAZOLIDINONES AND PREPARATION The present invention concerns novel-derivatives of S-aminornethyl-Z-oxazolldinones, their process of preparation and their therapeutic application.

The compounds according to the invention correspond to the general formula:

represents either a dialkylamino radical in which the alkyl portions have one to five carbon atoms, or a heterocyclic amino radical which may be substituted by an alkyl radical having one -to five carbon atoms or by a pyrrolidinocarbonylmethyl radical, and R represents a phenyl radical which may be substituted by one or more of the following radicals: an alkoxy radical having one to five carbon atoms; a halogen atom; a trifluoromethyl radical, or a carboxyl radical which may be esterifled. The process of preparing the compounds according to the present invention comprises treating a derivative of Z-propanol of the general fonnula:

1 (Ina-C H-CHr-N R -NH an n.

in which and R, have the same significance as in Formula (l), with ethyl carbonate; eliminating any excess ethyl carbonate and purifying the produce obtained by recrystallization.

The following preparations are given as non-limitative examples to illustrate the invention.

EXAMPLE] -Pyrrolidinomethyl-3-phenyl-2-oxazolidinone A mixture of 44 g. of l-pyrrolidino-3-phenylarnino-2 -propanol and 95 g. of ethyl carbonate is progressively heated to about 130C, which produces distillation of 2 several ml. of ethylcarbonate. The mixture is allowed to cool and when the temperature reaches l00C, 2 ml. of a solution of 15 percent sodium methylate in methanol is added thereto.

The mixture is then rapidly heated'to boiling and the ethanol foriiied during the reaction is distilled off.

When thisdistillation is compl eted the excess ethyl carbonate is removed under reduced pressure. A solid product is obtained which is crystallized in isopropyl ether.

Yield 59% I Melting point I 73C Empirical formula C H N,O,

Elementary analysis 7 C H N Calculated I: 68.27 7.37 l 1.37 Found 68.24 7.19 I 1.56

The base obtained by the above process, when treated with hydrochloric acid, yields the hydrochloride which melts, with decomposition, at 195C.

EXAMPLE I! 5-Dirnethylaininomethyl-3-phenyl-2-oxazolidinone twenty-five g. of l-dirnethylamino-3-phenylamino-2- propanol are added to 60 g. of ethyl carbonate. After the temperature of the mixture was increased to 100C, 5 ml. of a solution of 15 percent sodium methylate in methanol is added thereto. After distillation of the alcohol formed and the removal of excess ethyl carbonate, the residue obtained is taken up in 100 ml. of water and acidified with hydrochloric acid. The solution obtained is then washed with ether and rendered alkaline by the addition of soda. The resulting base is extracted with ether. On concentration of the ethen'fied solution, a crystallized residue is obtained which is recrystallized in heptanc.

Yield Melting point 48C Empirical formula C H -M0,

Elementary analysis: C H N Calculated b 65.43 7.32 12.7! Found '17 65.64 7.32 12.79

The hydrochloride is obtained by treating the base obtained by the above process in solution in acetone with hydrochloric acid. Melting point 238C EXAMPLE Ill Yield 65% Empirical formula C H N,O,

Melting point 102C Elementary analysis: C H N Calculated I: 64. it) 6.92 l0.68 Found I: 64.02 6.91 10.67

The hydrochloride, prepared by the action of hydrochloric acid on the base, melts at 210C.

recrystallized in isopropyl ether.

Yield 70% Melting point 53C Empirinal Iormula C H NJ), Elementary nnflylis: C H N Calculated I: 70.04 8.08 10.21 Found 5 70,17 7.97 10.32

The hydrochloride, prepared by the action of 15 The compounds listed in the following Table 1 have been prepared according to the process described in the preceding examples.

The compounds according to the invention have 5 been tested on animals in the laboratory and have shown,

in particular,

to possess hypotensive,

vasodilatatory, spasmolytic, sedative, myorelaxant, analgesic and anti-inflammatory properties. 1 Hypotensive action The administration of the compounds of the general Formula (I) provoke a durable diminution of the arterial pressure. There is equally observed a diminution of the contractile force and of the cardiac rhythm.

The results obtained with certain of the compounds of the general Formula (1) are shown in the following y r s ri ss ianfl sba tZ Z a TABLE I R; Elementary analysis N Melting Calculated Found Melting point, Yield, Empirical point, It, It; C, percent formula C H N C H N Salt C. b{ \N U Q 90 82 C15H21Na0: 65.43 7.69 15.26 65.59 7.71 16.31 2H0] 260 K Q 105 75 C1l MN2o2 69.20 7.74 10. 76 69.40 7.68 10.91 HCl 225 GO IL .1

C 86 66 CiaHirNrO; 62.38 7.25 11.19 62.53 7.37 11.28 I101 198 OCH:

CHI]

C OCHa 66 40 CuHnNzOr 58.05 7.16 9.03 67.97 7.16 9.22 1101 195 OCH :1 CH: I

OCHQ

CH; 62 55 CufluFNgO 60.49 1135 11.76 60.43 6.18 11.76 HCl 240 F CH1 Q 1 112 60 01111110151101 56.58 5.93 11.00 56.35 5.92 11.11 H61 210 C N\ TABLE ll R1 Administration Hypotension Animal Dose Value in Time in R2 R1 Salt treated perkg. Means percent minutes HCl Rabhit 1mg. IV 50 15 Cat 1mg. IV 35 CH: HCl IV 50 IV 25 P0 v HUI Rabbit 1mg. IV 15 N Cat v 1mg. IV 20 L 211C! 11m 5mg. W 011 10 -N N-Cll1 TABLE II -Conlinued Br I/ Administration Hypotension Animal Dose Value in Time in R2 R3 Salt treated per kg. Means percent minutes C) Q H01 Cat 1 2mg. Iv 40 a0 2HCl Cat 50m IV 50 30 a t Q g CH; H01 Cat 1 10mg IV 50 10 OCHa -N CH: OEH: HCI Cat 1 s. 20 mg IV 50 10 N OCHa OCH;

CH3 HCl Cat 12.5 mg. IV 50 10 F CH: HCl (at 10 mg. IV 45 10 -c1 1 Anesthetized.

I Son-anesthetized.

2. Vasodilatatory action The administration of the compounds of the general Formula l provoke, in the rabbit and the dog, a strong augmentation of the discharge of the femoral artery.

The results obtained with certain of the compounds Table Ill:

of the general Formula (I) are shown in the following 3. Spasmolytic action The compounds of the general Formula (1) exert an antagonistic action against the contractions provoked by barium chloride. This action, which is evidenced by Nora-IA means irltl'aart 'tl'lal.

VT-ABLE rv 6. Analgesic action The compounds of the general Formula (1) inhibit the contractiom observed in the mouse following the intraperitoneal injection of phenylbenzoquinone.

The results obtained with three compounds of the gelneral Formula (1) are shown in the following Table 7. Anti-inflammatory action The compounds of the general Formula l) exert an antagonistic action against carraghenine in the rat by inhibiting the formation of a localized oedema following the under-plantary injection of such substance.

By way of example, the DE 50 for the hydrochloride of 5-pyrrolidinomethyl-3-phenyl-2-oxazolidinone is /Ri DL50(lT1l('t?) in mgJltgJPO Protection Turning Traction against Turning R: R; Salt reflex strychnlne reflex HC] 115 200 x CH3 HCl 70 4. 90 -x HCl '5 a 225 Q 5. Sedative action TABLE \l The administration of the compounds of the general Formula (l) evidence such action by an inhibition of the locomotric activity of the mouse and a reinforce- R gal ml i (m 5" ment of the narcotic effects of pentluobarbital. L M

The results obtained with three compounds of the general Formula (I) are shown in the following Table V- (n, F m1 hfilitt' xv. ru

7 TABLE 40 /R1 0L, imice) in mg.,/lrg.l0 an, x mm 1 P t h.-dt u l .5 km 1' loiffi lfl l lll c l io rl ol e:- N 0 j I L U R2 R; Salt activity thiohar itol X/ HCl 100 H0 N/ ll(l \SII ukLR l' l cm 11c! s 200 mg./kg. by oral means, and for the hydrochloride N of 5-hexahydroazep1nomethyl-3-phenyl-2-ox- CH 50 amlidinone is mgJkg. by oral means. x6] 40 on As a result of the values obtained above and from the J following Table VII, the difference between the phar- C1 u 150 macologically active dose and the lethal dose is suffi- U x ciently large to enable the compounds of the general 55 Formula l to be utilized in therapeutics.

TABLE v11 RI DLm (mice) in mgJkg. intravenous Oral B: R; Salt means m ans HCl 550 -x cu, n r41 1:; ran

('1 is? mun an Q C 6 nm a? 550 N VII gonlinued DL (mice) in mgJkg. N Intravenous Oral It; H Salt means means 2 H01 100 -':Hz

CH; HCI 71.5

OCH; N

CH; OCH; HCl 193 OCH;

CH3 H01 125 F The utilization of the compounds of the ne Fob UCHPN RP R:

(1) in which:

is selected from the group consisting of dimethylamino, morpholino, hexahydroazepino,

pyrrolidino, N-methyl piperazino, N-pyrrolidinocarbonylmethyl piperazino and piperidino, and

R, is phenyl or phenyl substituted by one or more of the following radicals: an alkoxy radical having one to live carbon atoms; a halogen atom; a trifluoromethyl radical,

and the pharmaceutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1, in which the group is dimethylamino.

3. A compound as claimed in claim 1, in which the group is a pyrrolidino, morpholino, hexahydroazepino or piperidino radical.

4. A compound as claimed in claim I, in which the group is N-methylpiperazino or N-pyrrolidinocarbonylmethyl piperazino.

5. A compound as claimed in claim 1, in which the R is p-methoxyphenyl or (3,4,5-trimethoxy)phenyl.

6. A compound as claimed in claim 1, in which R, is p-tluorophenyl or p-chlorophenyl.

7. A compound according to claim 1, in which the group is dimethylamino and R, is phenyl.

i i i 

2. A compound as claimed in claim 1, in which the group is dimEthylamino.
 3. A compound as claimed in claim 1, in which the group is a pyrrolidino, morpholino, hexahydroazepino or piperidino radical.
 4. A compound as claimed in claim 1, in which the group is N-methylpiperazino or N-pyrrolidinocarbonylmethyl piperazino.
 5. A compound as claimed in claim 1, in which the R3 is p-methoxyphenyl or (3,4,5-trimethoxy)phenyl.
 6. A compound as claimed in claim 1, in which R3 is p-fluorophenyl or p-chlorophenyl.
 7. A compound according to claim 1, in which the group is dimethylamino and R3 is phenyl. 